Thrombin stimulation of inflammatory breast cancer cells leads to aggressiveness via the EGFR-PAR1-Pak1 pathway.
Thrombin stimulation of inflammatory breast cancer cells leads to aggressiveness via the EGFR-PAR1-Pak1 pathway.
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DOI：
10.5301/jbm.2012.10437
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发表时间：
2012-12-27
期刊：
影响因子：
--
通讯作者：
Kumar R
中科院分区：
文献类型：
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作者：
Ohshiro K;Bui-Nguyen TM;Divijendra Natha RS;Schwartz AM;Levine P;Kumar R
炎性乳腺癌（IBC）占上皮性乳腺癌的一小部分，但具有侵袭性。虽然凝血酶在癌症中的作用开始被揭示，但其对IBC生物学的影响仍然未知。本研究的目的是确定凝血酶对IBC细胞侵袭性的作用。在缺乏或存在表皮生长因子受体（EGFR）抑制剂厄洛替尼和蛋白酶激活受体1 （PAR1）抑制剂的情况下，用凝血酶处理IBC SUM149细胞系。考察了药物抑制剂对凝血酶促生长能力和侵袭性的影响。我们发现，抑制凝血酶作用的假定细胞靶点以浓度依赖的方式抑制SUM149细胞的生长和侵袭。此外，凝血酶介导的SUM149细胞迁移增加是通过EGFR磷酸化，进而以EGFR敏感的方式刺激p21活化激酶（Pak1）活性。有趣的是，凝血酶介导的Pak1通路刺激激活被厄洛替尼和par1抑制剂阻断。在原理验证研究中，我们发现了IBC中Pak1激活和PAR1表达的免疫组织化学证据。凝血酶利用EGFR传递信号，通过Pak1途径促进SUM149细胞生长和侵袭。该研究为未来通过靶向Pak1和/或EGFR减轻IBC侵袭性的治疗方法提供了理论依据。
Inflammatory breast cancer (IBC) accounts for a small fraction but aggressive form of epithelial breast cancer. Although the role of thrombin in cancer is beginning to be unfolded, its impact on the biology of IBC remains unknown. The purpose of this study was to establish the role of thrombin on the invasiveness of IBC cells. The IBC SUM149 cell line was treated with thrombin in the absence or presence of epidermal growth factor receptor (EGFR) inhibitor Erlotinib and protease-activated receptor 1 (PAR1)-inhibitor. The effects of pharmacological inhibitors on the ability of thrombin to stimulate the growth-rate and invasiveness were examined. We found that inhibiting putative cellular targets of thrombin action suppress both the growth and invasive of the SUM149 cells in a concentration-dependent manner. In addition, thrombin-mediated increased migration of SUM149 cells was routed through EGFR phosphorylation, and in-turn, stimulation of the p21-activated kinase (Pak1) activity in EGFR-sensitive manner. Interestingly, thrombin-mediated activation of the Pak1 pathway stimulation was blocked by Erlotinib and PAR1-inhibitor. For proof-of-principle studies, we found immunohistochemical evidence of Pak1 activation as well as expression of PAR1 in IBC. Thrombin utilizes EGFR to relay signals promoting SUM149 cell growth and invasion via Pak1 pathway. The study provides the rationale for future therapeutic approach in mitigating the invasiveness nature of IBC by targeting Pak1 and/or EGFR.